Metabolic syndrome is characterized by a combination of high blood pressure, insulin resistance with increased glucose production and decreased glucose utilization, central (abdominal) obesity, dyslipidemia (namely elevated triglycerides and reduced high-density lipoprotein cholesterol), and increased IL-6 and TN-α production.
Metabolic syndrome has emerged as an important cluster of risk factors for development of atherosclerotic diseases, e.g. prevalent and incident atherothrombotic cardiovascular disease (CVD), coronary heart disease, (CHD), stroke, peripheral arterial disease, chronic obstructive lung disease, as well as type 2 diabetes. Stimuli such as over-nutrition, physical inactivity and ageing may result in cytokine hyper-secretion and eventually lead to insulin resistance and diabetes in some, but not all, human subjects. According to the clinical criteria developed by the Adult Treatment Panel III (ATP III) Guidelines, it is estimated that 1 out of 4 adults living in the United States merits the diagnosis of metabolic syndrome; however, not all obese individuals develop this syndrome. Cardiovascular disease and Type 2 diabetes are leading causes of death and illness in developed countries, and these chronic diseases are becoming a dominating health problem worldwide. Early diagnosis of metabolic syndrome and prediction of early diagnosis of future cardiovascular events and diabetes would greatly improve the chances of successful prophylactic and therapeutic treatment.
Low-grade inflammation is a triggering factor of metabolic syndrome. Currently, blood levels of pro-inflammatory cytokines, hypersensitive C-reactive protein (hs-CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), serum amyloid A (SAA), fibrinogen and albumin; plasma viscosity; erythrocyte sedimentation rate (ESR); and leukocyte count are used to indicate the presence of low-grade inflammation and thereby predict the risk of developing metabolic syndrome, associated with vascular risk factors and with prevalent and incident atherothrombotic cardiovascular disease (CVD), coronary heart disease (CHD), stroke, peripheral arterial disease, chronic obstructive lung disease and type 2 diabetes.
Although apparently healthy individuals develop metabolic syndrome, it has, in recent years, become evident that HIV-infected individuals on treatment can also develop metabolic syndrome. The widespread implementation of Highly Active Anti-Retroviral Therapy (HAART) in western countries, from 1996 onwards, has increased the prevalence of long-living HIV-infected patients with suppressed HIV RNA and fairly high CD4 counts. However, adverse effects of HAART, in particular the administration of protease inhibitors, lead to a form of Metabolic Syndrome, similar to that observed in non-HIV infected obese individuals, including insulin resistance, fat redistribution, dyslipidemia and other risk factors of cardiovascular disease. There is thus a need to develop early diagnostic and predictive tools to prevent an increase in the morbidity and mortality of HIV-infected patients on HAART who display this cluster of dysmetabolic phenotypes. An individual's immunological status impacts his/her metabolic status, which is reflected in the level of immunological markers, e.g. TNF-α and IL-6. Such immunological markers have been shown to correlate inversely with symptoms of metabolic syndrome in HIV-infected patients as well as in HIV-negative subjects; however, data are not consistent and more stable and stronger predictive markers are needed.
Urokinase-type Plasminogen Activator Receptor (uPAR, CD87) is the cellular receptor for urokinase (uPA), and is expressed by most leukocytes, including monocytes, macrophages, neutrophils and platelets. uPAR is an activation antigen in monocytes and T cells. uPAR may be shed from the cell surface, generating a soluble form of the receptor (suPAR) lacking the GPI-anchor. The shedding mechanism is poorly understood but may occur by cleavage of the GPI-anchor catalyzed by a GPI-specific phospholipase D. Soluble forms of uPAR (suPAR) have been identified in cell culture supernatants and in diverse biological fluids such as tumor ascites, cystic fluid, serum, plasma and urine. The cellular origin of circulating suPAR is not known. Many, if not all, cells which express uPAR also shed soluble forms of the receptor when cultured in vitro.
Svendsen et al (2006) Surgical Infections 7, 463-471 disclosed that elevated preoperative concentrations of suPAR were associated with the development of pneumonia following surgery for colorectal cancer.
WO 2005/116077 disclosed the use of a ligand that binds to a binary uPA-uPAR complex, but which does not inhibit uPA-uPAR binding, in the treatment of a large number of diseases, including various cancers and cardiovascular diseases (such as atherosclerosis).